Transplantation of isolated pancreatic islets has become a popular experimental cure for diabetes. Many reports have demonstrated that the intraportal site is the most efficacious for islets. However, no studies have documented the effects of islet allograft rejection on the liver, an important task before clinical application. Preliminary reports on intrasplenic islet transplants have not documented in detail their physiologic or immunologic characteristics. Only a few reports allude to the mechanism of rejection of islets. Moreover, despite many studies confirming islet correction of insulin and glucose abnormalities, there are no documented reports of the role of islets in reversing the abnormal glucagon dynamics of diabetes. The proposed projects will investigate each of these areas in depth, using the streptozotocin diabetic rat model. Short and long term effects of islet allografts and isografts on liver morphology and function will be studied. Intrasplenic islet isografts and allografts will be compared to intraportal grafts to determine physiologic and immunologic differences. The role of antibody in islet allograft rejection will be defined with immunofluorescence methods. Standard absorption techniques will be used to define the islet specificity of antibody. Cell mediated immunity will be studied using 51Cr release assays. An enhancement model is to be investigated which specifically suppresses the immune response to donor tissue. The effects of islet grafts on abnormal glucagon metabolism will be studied. Alpha cell response of islet isograft recipients to arginine stimulation will be compared to normal and diabetic animals. Glucagon levels will be studied in allograft recipients to determine how rapidly alpha cell dysfunction is corrected, and how quickly it reappears following rejection. Perfusion studies of pancreas from isologous islet recipients should give information to confirm that alpha cell dysfunction is secondary to insulin lack in the diabetic animal.